miR-146a基因多态性可非经典靶定PPARγ调节动脉粥样硬化的机制研究

Atherosclerosis (AS) is a chronic progressive inflammatory process of the arterial wall and can be regulated by single nucleotide polymorphisms (SNP). I recently found that the SNP of rs2910164 is significantly related to the degree of coronary heart disease, the coronary score, the inflammatory factors, and the prognosis, which makes miR-146a cytosine (C) change to guanine (G). Undering cellular oxidation stress, it is oxidized to hydroxyguanosine (OH-G), the targeting RNA can be changed, non classical targeting PPARϒ mRNA induced downstream signaling pathways, thus speeding up the AS progress. On this basis, through in vivo and in vitro experiments, to Clarify the miR-146a (G) expression and subsequent oxidation determined by this SNP, explore the signal mechanism of ox-LDL in PPAR signaling and inflammatory activation, and explore the influence of SNP-miR (OH-G) -PPAR signaling pathway on macrophages and AS biology, and explore the new mechanism of action. This study not only helps to explain the susceptibility of clinical coronary heart disease (SNP), but also has early clinical recognition and targeted therapy for susceptible patients, which has practical clinical value.

动脉粥样硬化（AS）是动脉壁的慢性进行性炎症过程，可受到单核苷酸多态性（SNP）调节。本人最近发现rs2910164的SNP与冠心病的程度、冠脉积分、炎症因子及预后显著相关，其可使miR-146a的胞嘧啶（C）变为鸟嘌呤（G），并在细胞内氧化应激下，被氧化成羟基鸟苷酸（OH-G），使得其靶定的RNA发生变化，可非经典靶定PPARγ的mRNA，引起下游信号通路改变，从而加速AS的进展。本研究在此基础上，通过在体及离体实验，明确此SNP决定的miR-146a（G）表达及后续氧化，探寻ox-LDL通过此方式在PPAR信号及炎症激活中的信号机制，探明SNP-miR（OH-G）-PPAR信号通路对巨噬细胞及AS生物学产生影响及新的作用机制，本研究不但有助于解释临床冠心病SNP的易感性，且对易感患者具有早期识别及针对性治疗意义，具有实际的临床价值。

动脉粥样硬化（AS）是动脉壁的慢性进行性炎症过程，可受到单核苷酸多态性（SNP）调节。微小RNA (miRNA) 的多态性在急性冠脉综合征 (ACS) 中起重要作用。我们在人群中通过病例对照和队列的方式明确miR-146a rs2910164多态性与 ACS 风险以及经皮冠状动脉介入治疗（PCI）术后预后情况显著相关。并通过质谱、荧光素酶报告实验、免疫印迹和免疫组化等方式确定了其机制为：miR-146a rs2910164的等位基因胞嘧啶（C）突变为鸟嘌呤（G），在氧化应激的情况下G被氧化为羟基鸟苷酸（OH-G），使得其与IKBA的3'UTR错配并激活NF-κB炎症通路，进而加重粥样硬化斑块病变严重程度，影响PCI术后患者预后情况。所以，尽早检测ACS患者基因型并给予抗炎治疗，可改善患者生存质量。